Abstract

Tumor necrosis factor (TNF)-α is produced by cells of the immune system and is a key
mediator in immune and inflammatory reactions. Through interaction with widely expressed
receptors (TNF receptor 1 and TNF receptor 2), TNF-α is able to orchestrate the expression
of a range of downstream proinflammatory molecules. Over the past decade novel biologics
that inhibit TNF-α have been developed as extremely effective treatments for rheumatoid
arthritis. Structurally, these biologics are antibodies, or TNF receptors on an antibody
backbone that bind TNF-α directly and are delivered to patients by repeated injection.
Gene therapy offers an improved approach to delivering biologics as a single administration
of their encoding genetic material. In the present study we demonstrate the therapeutic
effect of a small molecular weight dimeric TNF receptor 2 (dTNFR) constitutively expressed
from plasmid DNA, delivered intramuscularly with electroporation, after disease onset
in a collagen-induced arthritis model. Regulated promoters that enable the production
of a transgene to be controlled are more suited to the application of gene therapy
in the clinic. Regulated expression of dTNFR from the plasmid pGTRTT was also therapeutic
in the mouse collagen-induced arthritis model when the inducer doxycycline was also
administered, whereas no therapeutic effect was observed in the absence of doxycycline.
The therapeutic effect of dTNFR expressed from a constitutive or regulated plasmid
was dependent on the degree of disease activity at the time of DNA injection. The
observations of this study are considered with regard to the disease model, the magnitude
of gene regulation, and the path to clinical application.